A. Depression and Traditional Treatment
Depression is one of the most prevalent and pervasive forms of mental illness that affects individuals across age and gender lines. (Gainotti et al. (2001) J. Neural Neurosurg. Psychiatr. 71: 258-261; Wong et al. (2001) Nature Rev. Neurosci. 2: 343-351; Nestler et al. (2002) Neuron 34: 13-25). The lifetime risk of major depression is about 12% in men and about 25% in women, generally, (Kessler et al. (1994) Arch. Gen. Psychiatry 51: 8). In addition, about 5 to 10% of all patients in the primary care environment, present with major depression, whereas about 3 to 5% of patients are diagnosed with dysthymia. (Barrett et al. (1988) Arch. Gen. Psychiatry 45: 1100). In an in-patient setting, however, between 10 and 14% of all patients are diagnosed with major depression. (Blackburn et al. (1997) Br. J. Psychiatry 171: 328). Major depression is a particularly disabling and pernicious, in part, because it is recurring. The rate of relapse for patients with major depression is about 40% over a two-year period after a first episode. The occurrence of relapse increases to about 75% within a five year period after the diagnosis of a second episode of major depression. (Solomon et al. (2000) Am. J. Psychiatry 157: 229).
Depressive disorders are most commonly treated with three main classes of compounds: 1) monamine oxidase inhibitors; 2) heterocyclic antidepressants; and 3) selective serotonin reuptake inhibitors (SSRIs). The known and currently prescribed antidepressants are by numerous side effects. Monoamine oxidase inhibitors were the first class of antidepressants used clinically. Monoamine oxidase inhibitors, including isocarboxazid, phenelzine, and tranylcypromine, inhibit the metabolism of phenylethylamine and catabolism of dopamine, serotonin and norepinephrine. As a consequence of numerous dietary restrictions associated with the use of monoamine oxidase inhibitors, extensive side effects, including hypertension, headache, myoclonic jerk, sleep disruption, and gastrointestinal complications, monoamine oxidase inhibitors are currently not used as a first-line antidepressant. The tricyclic antidepressants, including, imipramine, desipramine, nortrypline, amitrypline, doxepin and protrypline, produce a variety of anticholinergic side effects, drowsiness, orthostatic hypotension, cardiac arrhythmias and weight gain. Although generally milder than the monoamine oxidase inhibitors and the tricyclic antidepressants, SSRIs also produce numerous side effects. For example, SSRIs, including fluoxetine, paroxetine, fluvoxamine, sertraline, and citalopram, are associated with gastrointestinal distress, jitteriness, agitation and sleep disruption.
In addition to the numerous side effects associated with traditional antidepressant medications, these therapeutics are also characterized by marginal efficacy. Several studies on the efficacy of antidepressant therapy for major depression have concluded that the treatment of acute disease or maintenance therapy is associated with a 50-60% response rate. (Schulberg et al. (1998) Arch. Gen. Psychiatry 55: 1121). The average absolute response rate between antidepressants and placebo is about 20-25%. (Williams et al. (2000) Ann. Intern. Med. 132: 743). Consequently, there is a current need for new antidepressant therapies.
In view of the sometimes severe adverse side effects and marginal efficacy of numerous antidepressant therapies, there is a great need for improved pharmaceuticals that effectively treat depressive disorders without producing the side effects associated with treatments of depression. The present invention identifies those compounds that enhance or improve learning and memory as a new class of therapeutics for the treatment of depressive disorders.
B. Carbonic Anhydrase
Carbonic anhydrase, a zinc-containing enzyme that catalyzes the interconversion of carbon dioxide and bicarbonate anion, is present throughout the body, including the brain. (Sun et al. (2002) Trends in Pharm. Sci. 23(2): 83-89; incorporated herein by reference in its entirety). Carbonic anhydrase II, the most active of the seven human isozymes, is a 23.9 kDa enzyme found primarily in erythrocytes, glial cells and brain neurons. (Id). In addition to its involvement in pH regulation, bicarbonate reabsorption and carbon dioxide expiration, carbonic anhydrase plays a crucial role in signal processing, long-term synaptic transformation and attentional gating of memory storage. (Id.).
Carbonic anhydrase dysfunction has been associated with mental retardation, Alzheimer's disease, and impaired cognition. Conversely, the activation of carbonic anhydrase has been demonstrated to improve learning and memory. (Id.; U.S. Patent Application Serial Nos. PCT/US02/13784; PCT/US03/07102; 60/287,721; 60/362,081; Ser. Nos. 10/172,005; and 10/476,459; each incorporated herein by reference in its entirety). Prior to the present disclosure, however, the carbonic-anhydrase-mediated improvement of learning and memory has not been recognized as a mechanism for the treatment of depressive disorders. Although a recent biochemical study using isolated carbonic anhydrase identified three SSRIs, fluoxetine, sertraline and citalopram, as activators of carbonic anhydrase, these experiments did not demonstrate that carbonic anhydrase activation is the mechanism whereby the symptoms of depressive disorders are ameliorated. (Casini et al. (2003) Bioorg. Med. Chem. Lett. 13: 2765-2768).
Carbonic anhydrase activity is regulated by signaling pathways that include ryanodine receptor-mediated signaling pathways. The intracellular release of calcium through ryanodine receptors, for example, is involved in the GABA-mediated synaptic switch. (Sun et al. (2002) Trends in Pharmacol. Sci. 23(2): 83-89). Activation of ryanodine receptors in CA1 pyramidal cells, combined with depolarization induced calcium loading, transforms GABA-mediated responses, an effect that is blocked by ryanodine-receptor antagonists or carbonic anhydrase inhibitors. (Sun et al. (2000) Proc. Nat'l Acad Sci USA 97: 12300-12305). The effect of calcium on carbonic anhydrase, however, appears to be indirect. For example, early studies show that calcium potentiates the activation of either purified carbonic anhydrase or gastric mucosa carbonic anhydrase by histamine and other agents. (Puscas et al. (1996) J. Pharmacol. Exp. Ther. 277: 1464-1466). In addition, the dose-dependent inhibition of carbonic anhydrase by verapamil also implicates calcium in the activation of carbonic anhydrase. Furthermore, in human myelomonocytic cell lines, the synthesis of carbonic anhydrase II is activated by protein kinase C. (Sun et al. (2002) Trends in Pharmacol. Sci. 23(2): 83-89). Consequently, the PKC-mediated increase in carbonic anhydrase synthesis can increase carbonic anhydrase activity that has a resultant antidepressant effect.
C. Protein Kinase C
PKC has been identified as one of the largest gene families of non-receptor serine-threonine protein kinases. Since the discovery of PKC in the early eighties by Nishizuka and coworkers (Kikkawa et al. (1982) J. Biol. Chem. 257: 13341), and its identification as a major receptor for phorbol esters (Ashendel et al. (1983) Cancer Res., 43: 4333), a multitude of physiological signaling mechanisms have been ascribed to this enzyme. The intense interest in PKC stems from its unique ability to be activated in vitro by calcium and diacylglycerol (and its phorbol ester mimetics), an effector whose formation is coupled to phospholipid turnover by the action of growth and differentiation factors.
The activation of PKC has been shown to improve learning and memory. (U.S. Patent Application Serial Nos. PCT/US02/13784; PCT/US03/07102; 60/287,721; 60/362,081; Ser. Nos. 10/172,005; and 10/476,459; each incorporated herein by reference in its entirety). Prior to the present disclosure, however, the PKC-mediated improvement of learning and memory has not been recognized as a mechanism for the treatment of depressive disorders. Also, the PKC activators disclosed herein, specifically those compounds that improve learning and memory, were not recognized as possessing antidepressant activity.
D. Fibroblast Growth Factor-18 (FGF-18)
Fibroblast Growth Factor-18 (FGF-18) has been shown to improve learning and memory. (U.S. Provisional Application Ser. No. 60/429,321 and PCT/IB03/05408, which are both incorporated by reference herein in their entireties). Binding of FGF-18 to its cognate receptor activates a PKC-mediated signaling pathway that implicates both PKC and carbonic anhydrase. Prior to the present disclosure, however, the FGF-18-mediated improvement of learning and memory has not been recognized as a mechanism for the treatment of depressive disorders. Also, FGF-18 has not been recognized as possessing antidepressant activity.